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Inhibition of Poly(ADP-ribose) Polymerase Activation Attenuates β-Lapachone-Induced Necrotic Cell Death in Human Osteosarcoma Cells

https://doi.org/10.1006/taap.2002.9438Get rights and content

Abstract

β-Lapachone, a novel anticancer drug, induces various human carcinoma cells to undergo apoptotic cell death. However, we report here that, in human osteocarcinoma (U2-OS) cells, β-lapachone induces necrosis rather than apoptosis. β-Lapachone-induced necrotic cell death in U2-OS cells was characterized by propidium iodide uptake, cytochrome c release, a decreased mitochondrial membrane potential, and ATP depletion. The mitochondrial potential transition (MPT), including the reduction of the mitochondrial transmembrane potential and the release of mitochondrial cytochrome c, occurred in β-lapachone-treated cells; cotreatment of these cells with cyclosporin A, an inhibitor of MPT pore, failed to prevent necrotic cell death. This indicates that the MPT transition does not play a crucial role in this process. Furthermore, β-lapachone-induced necrosis was independent of oxidative stress and caspase activation. However, excessive poly(ADP-ribose) polymerase (PARP) activation and subsequent depletion of intracellular NAD+ and ATP were seen in β-lapachone-treated U2-OS cells. Cotreatment with a PARP inhibitor, 3-aminobenzamide, decreased β-lapachone-induced PARP activation and provided significant protection from necrosis by preventing depletion of intracellular NAD+ and ATP. Taken together, our results suggest that PARP plays an important role in the signaling pathway for β-lapachone-induced necrosis in U2-OS cells.

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    1

    These authors contributed equally to this work.

    2

    To whom correspondence should be addressed at Institute of Anatomy, School of Life Science, National Yang-Ming University, 155, 2nd Sec., Li-Nung Street, Shih-Pai, Taipei, Taiwan 112, Republic of China. Fax: 886–2-2821–2884; E-mail: [email protected].

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